The proposed Program Project participants at the San Francisco VAMC represent workers from several medical disciplines who are focusing their divergent scientific backgrounds on the study of epidermal function in relation to growth and differentiation, utilizing cultured human keratinocytes in a series of collaborative efforts. Keratinocytes serve as a superb model for the vectorial differentiation of epithelial structures. They are metabolically highly active, and exhibit a range of previously-unappreciated functions, and are available in large quantities, as homogeneous, cloned cell populations. Furthermore, their growth and differentiation in vitro can be manipulated in a variety of systems and assessed by distinctive morphological and biochemical markers. Already, several of the investigators have found dramatic changes in metabolism in relation to differentiation. This program project therefore represents a continuation and amalgamation of sevral interdependent research programs into a formalized, co-operative effort. Drs. Bikle and Pillai will study the metabolism of vitamin D and other cytokines in relation to keratinocyte differentiation, utilizing normal keratinocytes as well as aseries of squamous cell carcinoma cell lines that exhibit distinctive phenotypes. Dr. Boyer will study enzyme systems that metabolize exogenous drugs and chemicals in relation to keratinocyte differentiation. Drs. Elias, Monger and Williams will study the relationship of shingolipid metabolism to differentiation. Drs. Goldyne and Williams will study keratinocyte-fibroblast interactions addressing how keratinocyte interleukin I and fibroblast eicosanoids may regulate keratinocyte growth and differentiation. Dr. Grayson will determine how a recently identified family of hydrophobic, membrane proteolipids may regulate keratinocyte differentiation. Each principal investigator will rely on the expertise of the other project participants in order to enhance the productivity, breadth, and depth of his/her project, and the group as a whole will benefit from weekly research meetings, the in-put of an outside research advisory group, and an outside visitor/speaker program. The proposed program project thus represents a logical extension of our on-going research efforts into a more formalized, cohesive interaction that should produce importan new insights into epidermal function in relation to differentiation.